Abstract 7279: A novel humanized IL2 and IL15 receptor mouse model enables preclinical efficacy studies for IL-2 cancer therapeutics

Abstract Recombinant human interleukin 2 (IL-2) is effective in treating metastatic renal carcinoma and melanoma, however, severe dose-limiting toxicity restricts patient treatment. There is conflicting evidence from human and murine studies on whether activation of natural killer (NK) cells leads to efficacy or toxicity and if activation of T or NK cells is associated with therapeutic benefit. The development of a humanized mouse model for this system is imperative to evaluate the safety and efficacy of IL-2 targets. Here, we generated a homozygous humanized hIL-2RB/hIL-2RG/hIL-15/hIL-15RA mouse model which constitutively expresses human IL-2RB, IL-2RG, IL-15, and IL-15RA proteins. The distribution of basal leukocyte subpopulations of blood, spleen, and lymph nodes in humanized B-hIL-2RB/hIL-2RG/hIL-15/hIL-15RA mice is similar and comparable to the distribution found in wild-type C57BL/6 mice. Functionally, the human IL-2 and IL-15/IL-15RA complex elicits a dose-dependent induction of pSTAT5 in humanized mice. Furthermore, using this model, we have detected modest efficacy of a human IL-2 drug in inhibiting MC38 tumor growth in vivo. In summary, B-hIL-2RB/hIL-2RG/hIL-15/hIL-15RA mice provide a powerful preclinical model to clear roadblocks towards in vivo evaluation of IL-2 drugs for cancer treatment. Citation Format: Alexander Sercel, Linlin Wang, Suman Zhao, Zan Zhang, Zhenlan Niu, Yanling Wang, Xiaofei Zhou. A novel humanized IL2 and IL15 receptor mouse model enables preclinical efficacy studies for IL-2 cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7279.